Role of N-terminus in function and dynamics of sirtuin 7: an in silico study

Abstract

The sirtuin family comprises seven NAD⁺-dependent histone deacetylases named SIRT1 to SIRT7. The least investigated SIRT7 is currently considered as a promising therapeutic target for cardiovascular diseases, diabetes and different types of cancer. So far, its structure was not experimentally resolved, except of a fragment of its N-terminus. The aim of this study was to create in silico model of SIRT7 containing its core together with N-terminus, which is known to affect the enzyme’s catalytic activity and to find pockets that could be targeted by structure-based virtual screening. Homology model of SIRT7 was prepared using X-ray structures of other sirtuins and a resolved fragment of the N-terminus of SIRT7 as templates. All atom-unbiased molecular dynamics simulations were performed. It was found that N-terminus of SIRT7 remains in spatial proximity of the catalytic core for considerable fraction of time, and therefore, it may affect its catalytic activity by helping the enzyme to hold the substrate peptide. It may also participate in holding and release of the cofactor. Preferred orientations of NAD⁺ and acetyl-lysine inside SIRT7 were found, with all components forming a stable complex. Molecular dynamics provided an ensemble of conformations that will be targeted with virtual screening. Reliable in silico structure of SIRT7 will be a useful tool in searching for its inhibitors, which can be potential drugs in cancer treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sirtuin 7
• histone deacetylases
• HDACs
• lysine deacetylation
• molecular dynamics
• homology modelling
• H3 histone
• zinc modelling
• CADA
• NAD+

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Calculations were partially performed at the Okeanos supercomputer under a grant from the Interdisciplinary Center for Mathematical and Computational Modeling [grant number GA69-29] and under the PRACE project 14DECI0070, resource Archer, based on the United Kingdom at the University of Edinburgh. The study benefited from the project ‘The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases’, Operational Program Development of Eastern Poland 2007–2013, Priority Axis I modern Economy, operations I.3 Innovation promotion. Partnership for Advanced Computing in Europe AISBL.